Process for producing carbostyril derivatives

ABSTRACT

The present invention provides a process for producing carbostyril derivatives (I) which are known to be useful as medical drug such as antithrombotic agent, cerebral circulation improver, anti-inflammatory agent, antiulcer agent, etc. in a high yield and a high purity. The carbostyril derivatives (I) can be produced by reacting a carbostyril derivative (II) with a tetrazole derivative (III) in the presence of a phase transfer catalyst.

TECHNICAL FIELD

[0001] The present invention relates to a novel process for producingcarbostyril derivatives, and more particularly to a novel process forproducing carbostyril derivatives represented by the following generalformula (I):

[0002] wherein A represents a lower alkylene group; R represents acycloalkyl group; and the bond between the 3- and 4-positions of thecarbostyril skeleton represents a single bond or a double bond.

BACKGROUND ART

[0003] The compound represented by the above-mentioned general formula(I), namely the objective compound of the present invention, is known tobe useful as an antithrombotic agent, a cerebral circulation improver,an anti-inflammatory agent, an antiulcer agent, a hypotensive agent, anantiasthmatic agent, and a phosphodiesterase inhibitor, etc. (see:JP-A-56-49378 and U.S. Pat. No. 4,277,479).

[0004] The carbostyril derivatives represented by the general formula(I) have so far been produced by reacting a carbostyril derivativerepresented by the following general formula (II):

[0005] wherein the bond between the 3- and 4-positions of thecarbostyril skeleton is as defined above, with a tetrazole derivativerepresented by the following general formula (III′):

[0006] wherein X′ represents a halogen atom, and A and R are as definedabove, in the presence of an inorganic base or an organic base (see:JP-A-56-49378; U.S. Pat. No. 4,277,479; and Chem. Pharm. Bull., 31(4),1151-1157 (1983)).

DISCLOSURE OF THE INVENTION

[0007] According to the above-mentioned known process, the yield of thecompound of general formula (I) is as low as about 50 to 74%, becausethere is also formed a compound in which the tetrazole derivative ofgeneral formula (III′) has reacted not only with the hydroxyl group ofthe carbostyril derivative of general formula (II) but also with the1-position of the carbostyril derivative of general formula (II)simultaneously. Since the thus formed contaminative impurity isdifficult to remove, production of a compound of general formula (I)having a high purity has required a complicated process of purification.

[0008] It is an object of the present invention to provide a process forproducing a carbostyril derivative represented by the general formula(I) at a low cost and by a simple procedure. It is another object of thepresent invention to provide a process for producing a carbostyrilderivative represented by the general formula (I) without anycomplicated process of purification, in a high yield, and in a highpurity. It is yet another object of the present invention to provide anindustrially advantageous process for producing the carbostyrilderivatives represented by the general formula (I).

[0009] In view of the above-mentioned present situation, the presentinventors have conducted various studies with the aim of achieving theabove-mentioned objects. As a result, it has been found in the processof the studies surprisingly that, when a phase-transfer catalyst is usedas a catalyst, a compound of general formula (I) given by a reactionbetween the hydroxyl group of the carbostyril derivative of generalformula (II) and the tetrazole derivative of general formula (III′) isformed, and a compound given by the reaction between the 1-position ofthe carbostyril derivative of general formula (I) and the tetrazolederivative of general formula (III′) is scarcely formed, and thereaction progresses position-specifically, and thereby the objects ofthe present invention can be achieved. Based on this finding, thepresent invention has been accomplished.

[0010] According to the present invention, the objective carbostyrilderivative represented by the general formula (I) can be obtained in ahigh yield and a high purity by reacting a carbostyril derivativerepresented by the following general formula (II):

[0011] wherein the bond between the 3- and 4-positions of thecarbostyril skeleton represents a single bond or a double bond, with atetrazole derivative represented by the following general formula (III):

[0012] wherein X represents a halogen atom or a group causing the samesubstitution reaction as that caused by halogen atom, A represents alower alkylene group, and R represents a cycloalkyl group, in thepresence of a phase-transfer catalyst.

[0013] According to the process of the present invention, the hydroxylgroup of the carbostyril derivative of general formula (II) and thetetrazole derivative of the general formula (III) can be made to reactselectively and thereby the objective carbostyril derivative of generalformula (I) can be produced on an industrial scale, at a low cost, by asimple procedure, in a high yield and in a high purity.

BEST MODE FOR CARRYING OUT THE INVENTION

[0014] As examples of the lower alkylene group represented by A in thegeneral formulas (I) and (III) of this specification, mention can bemade of, straight chain or branched chain alkylene groups having 1-6carbon atoms such as methylene, ethylene, propylene, tetramethylene,2-ethylethylene, pentamethylene, hexamethylene, 2-methyltrimethylene,2,2-dimethyltrimethylene, 1-methyltrimethylene and the like. Among theselower alkylene groups, particularly preferred is tetramethylene group.

[0015] As the cycloalkyl group represented by R in the general formulas(I) and (III), mention can be made of, for example, cycloalkyl groupshaving 3-8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl and the like. Among these cycloalkylgroups, particularly preferred is cyclohexyl group.

[0016] As the halogen atom represented by X in the general formula(III), mention can be made of fluorine atom, chlorine atom, bromine atomand iodine atom, among which particularly preferred is chlorine atom.

[0017] As specific examples of the group causing the same substitutionreaction as that caused by the halogen atom represented by X in thecompound of general formula (III), mention can be made of loweralkanesulfonyloxy group, arylsulfonyloxy group, aralkylsulfonyloxy groupand the like. As specific examples of the lower alkanesulfonyloxy group,mention can be made of methanesulfonyloxy, ethanesulfonyloxy,isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy,tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy and thelike. As specific examples of the arylsulfonyloxy group, mention can bemade of substituted or unsubstituted arylsulfonyloxy groups such asphenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy,4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy,3-chlorophenylsulfonyloxy, α-naphthylsulfonyloxy and the like. Asspecific examples of the aralkylsulfonyloxy group, mention can be madeof substituted or unsubstituted aralkylsulfonyloxy groups such asbenzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy,4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy,4-nitrobenzylsulonyloxy, 4-methoxybenzylsulfonyloxy,3-chlorobenzylsulfonyloxy, α-naphthylmethylsuflonyloxy and the like.Among the groups represented by X, particularly preferred are halogenatoms.

[0018] As the bond between the 3- and 4-positions of the carbostyrilskeleton in the general formulas (I) and (II), a single bond isparticularly preferred.

[0019] Next, the process of the present invention will be explained inmore detail with reference to reaction schemes.

[0020] wherein X, A, R and the bond between the 3- and 4-positions ofthe carbostyril skeleton are as defined above.

[0021] In the reaction Scheme-1, the reaction between a compound ofgeneral formula (II) and a compound of general formula (III) is carriedout in an appropriate solvent in the presence of a phase-transfercatalyst and further a basic compound. As the solvent used herein, allthe inert solvents can be used so far as they exercise no adverseinfluence on the reaction. Examples of the solvent usable include water;alcohols such as methanol, ethanol, propanol, isopropyl alcohol,butanol, ethylene glycol and the like; ethers such as dimethyl ether,diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran,dioxane, monoglyme, diglyme and the like; ketones such as acetone,methyl ethyl ketone, ethyl isobutyl ketone and the like; aromatichydrocarbons such as benzene, o-dichlorobenzene, chlorobenzene, toluene,xylene and the like; esters such as methyl acetate, ethyl acetate, butylacetate and the like; aprotic polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide andthe like; and mixtures thereof. Among these solvents, particularlypreferred are mixtures of water and an aromatic hydrocarbon such asbenzene, o-dichlorobenzene, chlorobenzene, toluene, xylene and the like,and water itself alone.

[0022] As the basic compound, known ones can be used extensively.Examples thereof include inorganic bases such as sodium hydroxide,potassium hydroxide, cesium hydroxide, lithium hydroxide, sodiumcarbonate, potassium carbonate, cesium carbonate, lithium carbonate,sodium hydrogen carbonate, potassium hydrogen carbonate, silvercarbonate and the like; alkali metals such as sodium, potassium and thelike; alcoholates such as sodium methylate, sodium ethylate and thelike; metallic salts of organic acids such as sodium acetate and thelike; and organic bases such as triethylamine, diisopropylethylamine,pyridine, N,N-dimethylaniline, N-methylmorpholine,4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO) and the like. Among these bases, inorganic bases such aspotassium carbonate, cesium carbonate, lithium carbonate and the likeare particularly preferred.

[0023] As the phase transfer catalyst, mentioned can be made of, forexample, quaternary ammonium salts substituted with a residue selectedfrom the group consisting of straight or branched chain alkyl grouphaving 1-18 carbon atoms, phenyl lower alkyl group and phenyl group,such as tetrabutylammonium chloride, tetrabutylammonium bromide,tetrabutylammonium fluoride, tetrabutylammonium iodide,tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate,tributylmethylammonium chloride, tributylbenzylammonium chloride,tetrapentylammonium chloride, tetrapentylammonium bromide,tetrahexylammonium chloride, benzyldimethyloctylammonium chloride,methyltrihexylammonium chloride, benzylmethyloctadecanylammoniumchloride, methyltridecanylammonium chloride, benzyltripropylammoniumchloride, benzyltriethylammonium chloride, phenyltriethylammoniumchloride, tetraethylammonium chloride, tetramethylammonium chloride andthe like; phosphonium salts substituted with a residue selected from thegroup consisting of straight or branched chain alkyl groups having 1-18carbon atoms such as tetrabutylphosphonium chloride and the like; andpyridinium salts substituted with a straight or branched chain alkylgroup having 1-18 carbon atoms such as 1-dodecanylpyridinium chlorideand the like. Among these phase transfer catalysts, quaternary ammoniumsalts substituted with a straight or branched chain alkyl group having1-18 carbon atoms such as tetrabutylammonium chloride and the like areparticularly preferred. As the salt-forming ions in these salts,hydroxyl ion, hydrogen sulfate ion and halogen ions are preferred, amongwhich chlorine ion is particularly preferred. If desired, sodium sulfiteor the like may be added to the reaction system of the above-mentionedreaction for the purpose of preventing the coloration caused byoxidation.

[0024] The reaction is carried out usually at a temperature not lowerthan ambient temperature and not higher than 200° C., and preferably ata temperature of 50-150° C. The reaction time is usually from about onehour to about 10 hours. It is recommended to use the compound (III)usually in an amount of at least 0.5 mol and preferably 0.5-1.5 mol permol of the compound (II), to use the basic compound usually in an amountof 1-5 mol per mol of the compound (II), and to use the phase transfercatalyst usually in an amount of 0.1-1 mol and preferably 0.1-0.5 molper mol of the compound (II).

[0025] The compound of general formula (I) obtained by theabove-mentioned reaction can easily be isolated by the conventionalseparating means. As said separating means, mention can be made of, forexample, extraction method using a solvent, dilution method,recrystallization method, column chromatography, preparative thin layerchromatography, etc.

EXAMPLES

[0026] Next, the process of the present invention is more concretelyexplained below with reference to examples. The invention is by no meanslimited thereby.

Example 1

[0027] Into a three-necked flask having a capacity of 300 ml wereintroduced 10.00 g of 6-hydroxy-3,4-dihydrocarbostyril, 16.36 g of1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole, 10.16 g of potassiumcarbonate, 3.00 g of tetrabutylammonium chloride, 0.05 g of sodiumsulfite, 30 ml of toluene and 50 ml of water. The content of the flaskwas heated under reflux for 8 hours. After cooling the reaction mixtureto ambient temperature, the deposited crystalline product was collectedby filtration and washed with 50 ml of water. Then, the crude crystalthus obtained was introduced into 70 ml of 90% methanol cooled to 5° C.,and stirred at 5° C. for 10 minutes for the sake of washing. The crystalwas collected by filtration and further washed on the suction filterwith 20 ml of 90% methanol cooled to 5° C. The crystal was dried toobtain 21.46 g (yield 95%) of6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyrilas a colorless needle-like crystalline product.

[0028] Purity: 99.80%; m.p.: 158-159° C.

[0029] The purity was measured by high performance liquid chromatographyunder the following conditions:

[0030] Column: YMC Pack SIL A-002 (manufactured by YMC Co.)

[0031] Moving phase: dichloromethane/n-hexane/methanol=20/10/1

[0032] Detector: UV, 254 nm

[0033] Flow rate: 0.90 ml/min.

[0034] Retention time: 4.7 min.

Example 2

[0035] Into a flask having a capacity of 200 ml were introduced 12.00 gof 6-hydroxy-3,4-dihydrocarbostyril, 19.60 g of1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole, 8.20 g of 50% aqueoussolution of tetrabutylammonium chloride, 12.20 g of potassium carbonate,0.60 g of sodium sulfite and 60 ml of water. The content of the flaskwas heated under reflux for 8 hours with stirring. After the reaction,the reaction mixture was cooled to ambient temperature, and thedeposited crude crystal was once collected by filtration. After washingthe crystal firstly with 36 ml of methanol and then with 60 ml of water,the crystal was again introduced into a flask having a capacity of 200ml and heated under reflux together with 84 ml of methanol for 2 hours.The solution thus obtained was cooled to 10° C. The crystal wascollected by filtration, washed firstly with 24 ml of methanol and thenwith 24 ml of water, and dried at 80° C. Thus, 23.84 g (yield 87.7%) of6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyrilwas obtained as a colorless needle-like crystalline product.

[0036] Purity: 99.89%; m.p.: 158-159° C.

[0037] The purity was measured by high performance liquid chromatography(HPLC) under the same conditions as in Example 1.

1. A process for producing a carbostyril derivative represented by thefollowing general formula (I):

wherein A represents a lower alkylene group, R represents a cycloalkylgroup, and the bond between the 3- and 4-positions of the carbostyrilskeleton represents a single bond or a double bond, which comprisesreacting a carbostyril derivative represented by the following generalformula (II):

wherein the bond between the 3- and 4-positions of the carbostyrilskeleton is as defined above, with a tetrazole derivative represented bythe following general formula (III):

wherein X represents a halogen atom or a group causing the samesubstitution reaction as that caused by a halogen atom, and A and R areas defined above, in the presence of a phase transfer catalyst.
 2. Aprocess for producing a carbostyril derivative according to claim 1,wherein the reaction is carried out at a reaction temperature not lowerthan the ambient temperature and not higher than 200° C., in a solvent,in the presence of a basic compound.
 3. A process for producing acarbostyril derivative according to claim 2, wherein the reactiontemperature is 50° C. to 150° C.
 4. A process for producing acarbostyril derivative according to claim 2, wherein the solvent used isa mixture consisting of an aromatic hydrocarbon and water or wateralone, and said basic compound is an inorganic base.
 5. A process forproducing a carbostyril derivative according to claim 4, wherein saidaromatic hydrocarbon is benzene, o-dichlorobenzene, chlorobenzene,toluene or xylene, and said inorganic base is potassium carbonate,cesium carbonate or lithium carbonate.
 6. A process for producing acarbostyril derivative according to claim 1, wherein X in the tetrazolederivative represented by general formula (III) is a halogen atom.
 7. Aprocess for producing a carbostyril derivative according to claim 1,wherein X in the tetrazole derivative represented by general formula(III) is a group causing the same substitution reaction as that causedby a halogen atom, and said group is a lower alkanesulfonyloxy group, anarylsulfonyloxy group or an aralkylsulfonyloxy group.
 8. A process forproducing a carbostyril derivative according to claim 6, wherein X inthe tetrazole derivative represented by general formula (III) is achlorine atom.
 9. A process for producing a carbostyril derivativeaccording to claim 1, wherein said phase transfer catalyst is aquaternary ammonium salt substituted with a residue selected from thegroup consisting of straight or branched chain alkyl groups having 1-18carbon atoms, phenyl lower alkyl groups and phenyl groups, a phosphoniumsalt substituted with a straight or branched chain alkyl group having1-18 carbon atoms, or a pyridinium salt substituted with a straight orbranched chain alkyl group having 1-18 carbon atoms, and thesalt-forming ion in these salts is a hydroxyl ion, a hydrogen sulfateion or a halogen ion.
 10. A process for producing a carbostyrilderivative according to claim 9, wherein said phase transfer catalyst isa quaternary ammonium salt substituted with a residue selected from thegroup consisting of straight or branched chain alkyl groups having 1-18carbon atoms, phenyl lower alkyl groups and phenyl groups, and the saltforming ion in these said salt is a halogen ion.
 11. A process forproducing a carbostyril derivative according to claim 10, wherein saidphase transfer catalyst is a quaternary ammonium salt substituted with astraight or branched chain alkyl group having 1-18 carbon atoms.
 12. Aprocess for producing a carbostyril derivative according to claim 10,wherein said salt-forming ion in the salt is a chlorine ion.
 13. Aprocess for producing a carbostyril derivative according to claim 10,wherein said phase transfer catalyst is tetrabutylammonium chloride. 14.A process for producing a carbostyril derivative according to claim 13,wherein said phase transfer catalyst is used in an amount of 0.1 to 1mol per mol of the compound of general formula (II).
 15. A process forproducing a carbostyril derivative according to claim 14, wherein saidphase transfer catalyst is used in an amount of 0.1 to 0.5 mol per molof the compound of general formula (II).
 16. A process for producing acarbostyril derivative according to claim 1, which is a process forproducing6-[4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril.